Anosacral amyloidosis (ASA) is a rare type of primary cutaneous amyloidosis that has only been described in Asian populations and countries.1 The lesions present as well-demarcated, brown-colored patches or plaques, fanning out in lines from the anus to the sacral region. This presentation was first reported under the term "hyperkeratotic lichenified skin of the gluteal region" in 1979 in Japan.2 In 1981, a biopsy of the gluteal skin demonstrated amyloid deposition, and the diagnosis term of ASA was coined.
Background and purpose: The P2Y 14 receptor is activated by UDP‐sugars, most potently by UDP‐glucose, but not by free nucleotides, suggesting that UDP‐glucose is the cognate agonist for this receptor. However, evidence for regulated release of UDP‐glucose is scarce. In the present study, the occurrence of receptor‐promoted release of UDP‐glucose was investigated, using 1321N1 human astrocytoma cells. Experimental approach: UDP‐glucose release and hydrolysis were measured using HPLC‐based techniques. Phospholipase C activation and actin cytoskeleton reorganization were assessed by measuring inositol phosphate formation and fluorescence confocal microscopy, respectively. Key results: Thrombin and the protease‐activating receptor‐1 (PAR1) peptide TFLLRNPNDK (PAR1‐AP) evoked the release of UDP‐glucose and ATP, which was accompanied by enhanced inositol phosphate formation. Although carbachol promoted fourfold greater inositol phosphate formation than thrombin, it failed to promote nucleotide release. Thrombin‐promoted nucleotide release was inhibited by BAPTA‐AM, brefeldin A and cytochalasin D, and was insensitive to Pertussis toxin and PI3‐kinase inhibitors. Thrombin, but not carbachol, induced actin cytoskeleton reorganization, a hallmark of Rho activation in 1321N1 cells. However, PAR‐promoted UDP‐glucose release was not affected by Rho kinase inhibition. Conclusions and implications: PAR1‐evoked UDP‐glucose release reflected a Ca 2+ ‐dependent mechanism, engaging additional signalling independently of G i and Rho kinase activation and requiring a functional actin cytoskeleton and Golgi structures. Our study demonstrates the occurrence of Ca 2+ ‐dependent release of UDP‐glucose from astrocytoma cells in response to a physiologically relevant stimulus, that is, a G‐protein‐coupled receptor agonist. Given the presence of P2Y 14 receptors in astrocytes, UDP‐glucose may have important autocrine/paracrine functions in the brain. British Journal of Pharmacology (2008) 153 , 1528–1537; doi: 10.1038/sj.bjp.0707692 ; published online 21 January 2008
Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT).To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL.This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL.In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks.The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020.The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred.The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile.ClinicalTrials.gov Identifier: NCT02448381.
Pyoderma gangrenosum (PG) lacks consensus regarding treatment, and no prior studies assess treatment satisfaction in PG. The objective of this study was to determine patient-reported satisfaction in the treatment of PG, and associations with satisfaction. Methodology was a multicenter cross-sectional survey for patients who received systemic medication(s) to treat PG. Thirty-five patients completed the survey (mean age: 54.0 years, 65.7% female, response rate: 81.4%). Mean (± SD) SATMED-Q score was 75.0 (±16.2, range: 67.6-85.3). Older patients (72.6 ± 23.6 for 18-39 years, 74.4 ± 16.1 for 40-59, 77.1 ± 11.6 for 60+), plus those with higher incomes (72.9 ± 20.3 for $0-49 000; 74.0 ± 17.6 for $50 000-99 000; 79.0 ± 14.6 for $100 000+) and education status (69.4 ± 14.3 for high school equivalent, 72.9 ± 15.9 for undergraduate, 91.7 ± 10.6 for graduate), were more satisfied with treatment. Ulcerative PG had higher SATMED-Q scores (79.0 ± 13.2) than other subtypes (66.2 ± 19.3). For local therapy, wound care, or pain control, 63.2%, 100%, and 75% were satisfied, respectively. The mean DLQI was 8.6 (±7.6, range: 0-29), and higher DLQI was associated with decreased satisfaction. Satisfaction with providers was positively correlated with global satisfaction (Pearson's r = 0.638). The presence of pain and/or depression influenced both SATMED-Q (72.8 ± 18.8 with pain, 78.3 ± 11.2 without; 68.2 ± 18.8 with depression, 80.1 ± 12.2 without) and DLQI scores (12.1 ± 8.1 with pain, 3.9 ± 3.4 without; 10.3 ± 7.1 with depression, 7.4 ± 8.0 without). To optimize the patient experience, non-modifiable associations should be individually considered, and potentially modifiable associations such as satisfaction with specific providers, pain, and depression, may be targeted for management.
Supplementary Table from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma
Supplementary Table from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma
